PROJECT SUMMARY/ABSTRACT Sleep apnea is the most common form of sleep disordered breathing and patients with sleep apnea exhibit persistent activation of the sympathetic nervous system ? which has known negative consequences, including the development of chronic hypertension. Intermittent hypoxia (IH) has been implicated as the primary stimulus for evoking increases in sympathetic activity and resultant hypertension with recurrent apneas. Evidence from animals suggests the persistent rise in sympathetic nervous system activity with IH occurs through changes in both chemoreflex and baroreflex function; however, little is known regarding the contribution of these reflexes to sympathetic discharge patterns in humans. Along these lines, research in animals supports a contribution of endothelin-1 to autonomic changes with IH, however these findings have yet to be translated to humans. Thus, the overall goal of this K99/R00 application is to better understand the effect of IH on sympathetic neuronal discharge patterns in humans, as well as mechanisms that mediate persistent sympathoexcitation with IH. We will use measures of sympathetic nervous system activity and a novel action potential analysis approach to test ideas about reflex-mediated sympathetic discharge patterns and contributing mechanisms in IH. In Aim 1, we will characterize sympathetic neuronal discharge patterns in response to acute IH in healthy humans. In Aim 2, we will use acute hyperoxia to identify the contribution of the carotid chemoreflex to sympathetic nervous system activation with IH. In Aim 3, we will use intravenous phenylephrine to identify the contribution of the baroreflex to sympathetic nervous system activation with IH. In Aim 4, we will identify the contribution of endothelin-1 to sympathetic discharge patterns with IH and its role in chemoreflex- and baroreflex-mediated changes in sympathetic nervous system activity. The proposed novel human studies are designed to provide a major step forward in understanding the link between IH and persistent sympathoexcitation ? and by extension, hypertension and associated cardiovascular disease risk in humans with sleep apnea. To our knowledge, this is the first effort to understand sympathetic discharge patterns in response to IH in humans from both a descriptive (Aim 1) and mechanistic (Aims 2-4) standpoint. Importantly, we will collect basic physiological data under tightly-controlled conditions in healthy humans to systematically examine the effect of IH and identify key contributing mechanisms on sympathetic control that will be critical to our understanding prior to targeted work in patients with sleep apnea. By better understanding the effect of acute IH on sympathetic activity, therapeutic approaches can be designed to systematically normalize sympathetic control of the cardiovascular system in conditions of IH (e.g. sleep apnea) to prevent the development of hypertension and other complications related to sympathetic over-activity. Furthermore, these projects will serve as a vehicle to build upon the Applicant's training in neurovascular control and her recently completed F32-funded work by providing opportunities for her to gain additional knowledge and learn new experimental techniques and approaches. Importantly, this will also generate an investigative niche for the Applicant's intellectual and technical skill sets that will launch her independent career.